The overall goal of this proposal is to advance knowledge on the development of depression in children and adolescents by investigating gene-environment interplay associated with endophenotypes for depression. Understanding how genes and the environment interact to predict endophenotypes will help to increase knowledge on developmental pathways to depression initiated by genetic vulnerabilities. Specifically, theory suggests that phenotypes related to negative emotionality/temperament may be an intermediate trait between candidate genes and depression (Caspi, Hariri, Holmes, Uher, &Moffitt, 2010). Yet, no study to date has examined gene x environment (g x e) interactions predicting observed emotional responses elicited in the laboratory among adolescents. Furthermore, the study of the development of depression among youth is especially important given that adolescent-onset depression is associated with a 2-7 times increased likelihood of recurrence in adulthood (Rutter, Kim-Cohen, &Maughan, 2006). Therefore, to inform prevention efforts it is important to predict adolescent-onset depression before recurrent episodes occur. The study of developmental pathways to depression is consistent with the mission of the National Institute of Mental Health to understand trajectories of mental illness that can help determine how best to intervene. In addition, the proposed project will target the NIMH Division of Developmental Translational Research areas of high priority by 1) focusing on identifying behavioral phenotypes reflecting mood regulation/negative emotionality that will help to discover underlying genetic vulnerabilities, 2) testing a model that incorporates genetics, negative emotionality, and experiental/environmental factors in the development of depression, and 3) employing a longitudinal design to examine pathways for depression and trajectories of increasing depression. Additionally, this proposal seeks to address limitations of prior g x e studies of depression by employing a multi-method, multi-informant, multi-wave design to carefully assess environmental variables (chronic stress) as well as depression diagnoses and symptoms among 365 3rd, 6th, and 9th graders across 7 waves of data with regular follow-ups every 3 months over a period of 18 months. Moreover, the proposed research will employ strong methodology to assess the potential endophenotype of negative emotionality by observing emotions [elicited in the laboratory during a conflict discussion.] Finally, the research will examine 3 carefully selected and theoretically motivated candidate genes: the serotonin transporter gene (5-HTTLPR), the dopamine D2 receptor gene (DRD2), and monoamine oxidase A (MAOA). The research will test clear a priori hypotheses about the developmental pathways through which these candidate genes may influence depression. PUBLIC HEALTH RELEVANCE: The World Health Organization states that depression accounts for the greatest proportion of disease burden attributed to non-fatal illnesses (Utsun &Chatterji, 2001), and many individuals experience their first clinically significant depression during adolescence (Hankin et al., 1998). Furthermore, the study of the development of depression during adolescence is especially important given that adolescent-onset depression is associated with a 2-7 times increased likelihood of recurrence in adulthood (Rutter, Kim-Cohen, &Maughan, 2006). Therefore, the proposed research aims to study developmental pathways to depression among youth to inform prevention efforts before recurrent episodes occur.